Pyrazolo[1,5-a]pyrimidine derivatives

ABSTRACT

The present invention provides pyrazolo[1,5-a]pyrimidine derivatives represented by the formula (1)                    
     wherein R 1  represents lower alkyl or the like; one of R 2  and R 3  represents hydrogen and the other represents phenyl having lower alkoxy or the like, and R 4  is hydrogen, carboxyl, lower alkoxy-carbonyl or the like. The derivatives of the invention have pharmacological effects such as analgesic action, inhibitory effect on nitrogen monoxide synthetase and the like and are useful as analgesics. The derivatives of the invention are also useful as therapeutic or prophylactic agents for septicemia, endotoxin shock, chronic articular rheumatism, etc.

CROSS REFERENCE TO RELATED APPLICATIONS

Applicants claim priority under 35 U.S.C. §119 of RUSSIA Application No.98109664 filed on May 19, 1998. Applicants also claim priority under 35U.S.C. §120 of PCT/RU99/00166 filed on May 19, 1999. The internationalapplication under PCT article 21(2) was not published in English.

TECHNICAL FIELD

The present invention relates to novel pyrazolo[1,5-a]pyrimidinederivatives.

BACKGROUND ART

The pyrazolo[1,5-a]pyrimidine derivatives of the invention are novelcompounds that have never been described in the literature.

DISCLOSURE OF INVENTION

An object of the present invention is to provide compounds useful asmedicine.

The present invention provides novel pyrazolo[1,5-a]pyrimidinederivatives represented by the following formula (1)

wherein

R¹ is lower alkyl, phenyl or thienyl;

one of R² and R³ is hydrogen and the other is naphthyl, furyl, pyridyl,styryl, phenylethynyl, substituted phenyl having 1 to 3 substituentsselected from the group consisting of lower alkoxy, phenyl-lower alkoxyand hydroxyl, or phenyl which may have a substituent selected from thegroup consisting of lower alkylthio, N,N-di-lower alkylamino,halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy andhalogen;

R⁴ is hydrogen, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, carboxyl, lower alkoxy-carbonyl, lower alkyl,phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3substituents selected from the group consisting of lower alkoxy, halogenand nitro, phenoxycarbonyl which may have halogen or nitro as asubstituent, carbamoyl, N-lower alkyl-carbamoyl, N-benzylcarbamoyl,N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl, N-(carboxy-loweralkyl)carbamoyl, N-halophenylcarbamoyl, N-(1-loweralkoxy-carbonyl-2-phenylethyl)carbamoyl,N-(1-carboxy-2-phenylethyl)carbamoyl, phenyl which may have halogen as asubstituent, or the group

 wherein R¹, R² and R³ are as defined above.

When R² is hydrogen, R³ and R⁴ may conjointly form a group representedby

wherein the R⁵s are the same or different and independently representhydrogen or lower alkoxy.

In the specification, the term “lower alkyl” includes alkyl groupshaving 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, hexyl and the like.

The thienyl group include 2-thienyl and 3-thienyl.

The naphthyl group includes 1-naphthyl and 2-naphthyl.

The furyl group includes 2-furyl and 3-furyl.

The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl.

The lower alkoxy group includes alkoxy groups having 1 to 6 carbonatoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,pentyloxy, hexyloxy and the like.

The phenyl-lower alkoxy group as a substituent of the substituted phenylgroup includes phenyl-substituted alkoxy groups having 1 to 6 carbonatoms, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy,3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy andthe like.

The substituted phenyl group having 1 to 3 substituents selected fromthe group consisting of lower alkoxy, phenyl-lower alkoxy and hydroxylinclude 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-propoxyphenyl, 4-buthoxyphenyl, 4-pentyloxyphenyl,4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl,3,4-dibutoxyphenyl, 3,4-dipentyloxyphenyl, 3,4-dihexyloxyphenyl,3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl,2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl,3,4,5-triethoxyphenyl, 3,4,5-tripropoxyphenyl, 3,4,5-tributoxyphenyl,3,4,5-tripentyloxyphenyl, 3,4,5-trihexyloxyphenyl, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl,4-benzyloxyphenyl, 4-(2-phenylethoxy)phenyl, 4-(3-phenylpropoxy)phenyl,4-(4-phenylbutoxy)phenyl, 4-(5-phenylpentyloxy)phenyl,4-(6-phenylhexyloxy)phenyl, 4-hydroxy-3-methoxyphenyl,3-hydroxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl,3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-hydroxyphenyl,3-benzyloxy-4-hydroxyphenyl, 3-hydroxy-4,5-dimethoxyphenyl,4-hydroxy-3,5-dimethoxyphenyl, 3-benzyloxy-4,5-dimethoxyphenyl,4-benzyloxy-3,5-dimethoxyphenyl, 3,4-dihydroxyphenyl,3,4-dibenzyloxyphenyl, 3,4,5-trihydroxyphenyl, 3,4,5-tribenzyloxyphenyland the like.

The lower alkylthio group as a substituent on the phenyl group which mayhave a substituent selected from the group consisting of loweralkylthio, N,N-di-lower alkylamino, halogen-substituted lower alkyl,phenyl, nitro, methylenedioxy and halogen includes, for example,alkylthio groups having 1 to 6 carbon atoms, such as methylthio,ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

The N,N-di-lower alkylamino group as a substituent on the phenyl groupincludes, for example, N,N-di-(C₁₋₆-alkyl)amino groups such asN,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino,N,N-dibutylamino, N,N-dipentylamino, N,N-dihexylamino and the like.

The halogen-substituted lower alkyl group as a substituent on the phenylgroup includes, for example, perhalogeno-(C₁₋₆-alkyl) groups (whereinhalogeno is selected from fluorine, chlorine, bromine and iodine).Specific examples include trifluoromethyl, pentafluoroethyl,heptafluoropropyl, nonafluorobutyl, undecafluoropentyl,tridecafluorohexyl and the like.

The halogen atom as a substituent on the phenyl group includes fluorine,chlorine, bromine and iodine.

Examples of the phenyl group which may have a substituent selected fromthe group consisting of lower alkylthio, N,N-di-lower alkylamino,halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy andhalogen are unsubstituted phenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 4-ethylthiophenyl,4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl,4-hexylthiophenyl, 2-(N,N-dimethylamino)phenyl,3-(N,N-dimethylamino)phenyl, 4-(N,N-dimethylamino)phenyl,4-(N,N-diethylamino)phenyl, 4-(N,N-dipropylamino)phenyl,4-(N,N-dibutylamino)phenyl, 4-(N,N-dipentylamino)phenyl,4-(N,N-dihexylamino)phenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl,4-nonafluorobutylphenyl, 4-undecafluoropentylphenyl,4-tridecafluorohexylphenyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-methylenedioxyphenyl,3,4-methylenedioxyphenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl and the like.

Examples of the lower alkylthio group include those mentioned above as asubstituent on the phenyl group.

The lower alkylsulfinyl group includes, for example,(C₁₋₆-alkyl)sulfinyl groups such as methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and thelike.

The lower alkylsulfonyl group includes, for example,(C₁₋₆-alkyl)sulfonyl groups such as methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and thelike.

The lower alkoxy-carbonyl group includes (C₁₋₆-alkoxy)carbonyl groupssuch as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The substituted benzyloxycarbonyl group having 1 to 3 substituentsselected from the group consisting of lower alkoxy, halogen and nitroincludes, for example, 2-methoxybenzyloxycarbonyl,3-methoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3-ethoxybenzyloxycarbonyl, 3-propoxybenzyloxycarbonyl,3-butoxybenzyloxycarbonyl, 3-pentyloxybenzyloxycarbonyl,3-hexyloxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 4-iodobenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,3-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,2,3-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,3-dichlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,3,4-dichlorobenzyloxycarbonyl, 3,5-dichlorobenzyloxycarbonyl,2,4-dinitrobenzyloxycarbonyl, 3,5-dinitrobenzyloxycarbonyl,2,3,4-trimethoxybenzyloxycarbonyl, 2,3,5-trimethoxybenzyloxycarbonyl,2,3,6-trimethoxybenzyloxycarbonyl, 2,4,5-trimethoxybenzyloxycarbonyl,2,4,6-trimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl,2,4,6-trichlorobenzyloxycarbonyl, 2,4,6-trinitrobenzyloxycarbonyl andthe like.

The phenoxycarbonyl group which may have halogen or nitro as asubstituent includes, for example, 2-chlorophenoxycarbonyl,3-chlorophenoxycarbonyl, 4-chlorophenoxycarbonyl,4-bromophenoxycarbonyl, 4-iodophenoxycarbonyl, 4-fluorophenoxycarbonyl,2-nitrophenoxycarbonyl, 3-nitrophenoxycarbonyl, 4-nitrophenoxycarbonyland the like.

The N-lower alkyl-carbamoyl group includes N-(C₁₋₆-alkyl)carbamoylgroups such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl,N-hexylcarbamoyl and the like.

The N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl group includesN-[(C₁₋₆-alkoxy)carbonyl(C₁₋₆-alkyl)]carbamoyl groups such asN-(methoxycarbonylmethyl)carbamoyl, N-(ethoxycarbonylmethyl)carbamoyl,N-(propoxycarbonylmethyl)carbamoyl, N-(butoxycarbonylmethyl)carbamoyl,N-(pentyloxycarbonylmethyl)carbamoyl,N-(hexyloxycarbonylmethyl)carbamoyl,N-(2-methoxycarbonylethyl)carbamoyl,N-(3-methoxycarbonylpropyl)carbamoyl,N-(4-methoxycarbonylbutyl)carbamoyl,N-(5-methoxycarbonylpentyl)carbamoyl,N-(6-methoxycarbonylhexyl)carbamoyl and the like.

The N-(carboxy-lower alkyl)carbamoyl group includesN-(carboxy-C₁₋₆-alkyl)carbamoyl groups such asN-(carboxymethyl)carbamoyl, N-(2-carboxyethyl)carbamoyl,N-(3-carboxypropyl)carbamoyl, N-(4-carboxybutyl)carbamoyl,N-(5-carboxypentyl)carbamoyl, N-(6-carboxyhexyl)carbamoyl and the like.

The N-halophenylcarbamoyl group includes N-phenylcarbamoyl groups havingon the phenyl ring a halogen atom selected from fluorine, chlorine,bromine and iodine.

Specific examples are N-(2-chlorophenyl)carbamoyl,N-(3-chlorophenyl)carbamoyl, N-(4-chlorophenyl)carbamoyl,N-(2-bromophenyl)carbamoyl, N-(3-bromophenyl)carbamoyl,N-(4-bromophenyl)carbamoyl, N-(2-iodophenyl)carbamoyl,N-(3-iodophenyl)carbamoyl, N-(4-iodophenyl)carbamoyl,N-(2-fluorophenyl)carbamoyl, N-(3-fluorophenyl)carbamoyl,N-(4-fluorophenyl)carbamoyl and the like.

The N-(1-lower alkoxy-carbonyl-2-phenylethyl)carbamoyl group includesN-[1-(C₁₋₆-alkoxy)carbonyl-2-phenylethyl]carbamoyl groups such asN-(1-methoxycarbonyl-2-phenylethyl)carbamoyl,N-(1-ethoxycarbonyl-2-phenylethyl)carbamoyl,N-(1-propoxycarbonyl-2-phenylethyl)carbamoyl,N-(1-butoxycarbonyl-2-phenylethyl)carbamoyl,N-(1-pentyloxycarbonyl-2-phenylethyl)carbamoyl,N-(1-hexyloxycarbonyl-2-phenylethyl)carbamoyl and the like.

The phenyl group which may have halogen as a substituent Includesunsubstituted phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl,4-iodophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and thelike.

The pyrazolo[1,5-a]pyrimidine derivatives of the present invention havepharmacological effects such as analgesic action, inhibitory effect onnitrogen monoxide synthetase and the like and are useful as analgesics.The derivatives of the invention are also useful as therapeutic orprophylactic agents for septicemia, endotoxin shock, chronic articularrheumatism, etc.

Examples of the derivatives of the invention preferable for medical useinclude the following (i) and (ii):

(i) compounds of formula (1) wherein R¹ is lower alkyl; and

(ii) compounds of formula (1) wherein R¹ is phenyl or thienyl, one of R²and R³ is hydrogen and the other is substituted phenyl having 1 to 3lower alkoxy groups as substituents and R⁴ is hydrogen, carboxyl orlower alkoxy-carbonyl.

Among the compounds (i), the following compounds (1a), (1b) and (1c) aremore preferred:

(1a) compounds wherein R¹ is lower alkyl and R⁴ is hydrogen, carboxyl orlower alkoxy-carbonyl;

(1b) compounds wherein R¹ is lower alkyl and one of R² and R³ ishydrogen and the other is phenyl having 1 to 3 lower alkoxy groups assubstituents, R⁴ is lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, lower alkyl, phenylthiomethoxycarbonyl, substitutedbenzyloxycarbonyl having 1 to 3 substituents selected from the groupconsisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which mayhave halogen or nitro as a substituent, carbamoyl, N-loweralkyl-carbamoyl, N-benzylcarbamoyl, N-(lower alkoxy-carbonyl-loweralkyl)carbamoyl, N-(carboxy-lower alkyl)carbamoyl,N-halophenylcarbamoyl, N-(1-loweralkoxy-carbonyl-2-phenylethyl)carbamoyl, or the group

wherein R¹, R² and R³ are as defined in formula (1) and preferably thesame as described in this section (1b); and

(1c) compounds wherein R¹ is lower alkyl and R² is hydrogen and R³ andR⁴ conjointly constitute a group represented by

wherein the R⁵s are the same or different and independently representhydrogen or lower alkoxy.

Of the compounds (1a) to (1c), especially suitable for medical use arethose wherein R¹ is lower alkyl, more preferably n-butyl.

More preferred of the compounds (ii) are those wherein R¹ is phenyl orthienyl, one of R² and R³ is hydrogen and the other is phenyl having 1to 3 lower alkoxy groups as substituents and R⁴ is hydrogen, carboxyl orlower alkoxy-carbonyl.

Other preferable groups of compounds of the invention include a group ofcompounds (a) wherein R¹ is n-butyl, R² is hydrogen, R³ is naphthyl,pyridyl, phenyl having 1 to 3 lower alkoxy groups as substituents orhalogen-substituted phenyl and R⁴ is hydrogen or lower alkylthio; and agroup of compounds (b) wherein R¹ is n-propyl or n-butyl, R² issubstituted phenyl having 1 to 3 substituents selected from the groupconsisting of lower alkoxy, phenyl-lower alkoxy and hydroxyl, or phenylwhich may have a substituent selected from the group consisting ofN,N-di-lower alkylamino, halogen-substituted lower alkyl and halogen, R³is hydrogen and R⁴ is carboxyl, lower alkoxy-carbonyl,phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3substituents selected from the group consisting of lower alkoxy, halogenand nitro, phenoxycarbonyl which may have halogen or nitro as asubstituent, or the group

wherein R¹, R² and R³ are as defined above in formula (1) and preferablythe same as shown in this section (b).

Most preferable compounds of the invention for medical use includecompounds wherein R¹ is n-butyl, R² is hydrogen, R³ is pyridyl, morepreferably 2-pyridyl and R⁴ is hydrogen, and compounds wherein R¹ isn-butyl, R² is phenyl having 3 lower alkoxy groups as substituents orphenyl having 2 lower alkoxy groups and 1 hydroxyl group assubstituents, more preferably 3,4,5-trimethoxyphenyl, R³ is hydrogen andR⁴ is carboxyl.

Methods for producing the derivatives of the invention are describedbelow in detail.

The derivatives of the present invention can be produced, for example,by processes shown below in Reaction Scheme-1 to Reaction Scheme-10.

wherein R¹, R² and R³ are as defined above, X represents halogen, Q andZ independently represent lower alkyl, ψ is naphthyl, furyl, pyridyl,styryl, phenylethynyl, substituted phenyl having 1 to 3 substituentsselected from the group consisting of lower alkoxy, phenyl-lower alkoxyand hydroxyl, or phenyl which may have a substituent selected from thegroup consisting of lower alkylthio, N,N-di-lower alkylamino,halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy andhalogen.

The halogen atom represented by X includes fluorine, chlorine, bromineand iodine.

According to Reaction Scheme-1, a known compound (2) is reacted with aknown compound (3) to produce a compound (4). The compound (4) isconverted to a compound (5), which is then reacted with a known compound(6) to produce a compound (1a) of the present invention.

The reaction between the compound (2) and compound (3) can be carriedout in the presence of a base in a suitable inert solvent attemperatures in the range of 0° C. to room temperature. Examples ofinert solvents include N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), tetrahydrofuran (THF), dimethoxyethane(DME), benzene, toluene and the like. Examples of bases include sodiumhydride, potassium hydride, sodium ethoxide, potassium-t-butoxide andthe like. Each of the compound (3) and the base is usually used in anequimolar amount to an about 5-fold molar amount, relative to thecompound (2). The reaction is completed in about 2 to about 100 hours.

The compound (4) thus obtained is treated with an aqueous alkalisolution such as an aqueous sodium hydroxide solution, aqueous potassiumhydroxide solution or the like at temperatures in the range of roomtemperature to about 100° C. for about 30 minutes to about 5 hours, thusconverting to the compound (5). Since the aqueous alkali solutionfunctions as a solvent in the above treatment reaction, it isunnecessary to use other solvents. However, other inert solvents such asmethanol, ethanol and the like may be used.

The compound (5) resulting from the above reaction is reacted with analdehyde derivative (6) to convert to a compound (1a) of the presentinvention. The reaction can be carried out using an aqueous alkalisolution such as aqueous sodium hydroxide solution, aqueous potassiumhydroxide solution or the like in an inert solvent such as methanol,ethanol or the like at temperatures in the range of about −10° C. toroom temperature for about 10 minutes to about 3 hours. Each of thealdehyde derivative (6) and the aqueous alkali solution is used in anequivalent amount to a slight excess, relative to the compound (5).

The reactions for converting the compound (4) to the compound (5) andsynthesizing the compound (1a) therefrom shown in Reaction Scheme-1 maybe sequentially carried out in the same reactor.

wherein R¹, Q, X and ψ are as defined above, R^(2a) is naphthyl, furyl,pyridyl, styryl, phenylethynyl, substituted phenyl having 1 to 3substituents selected from the group consisting of lower alkoxy,phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituentselected from the group consisting of lower alkylthio, N,N-di-loweralkylamino, halogen-substituted lower alkyl, phenyl, nitro,methylenedioxy and halogen.

In Reaction Scheme-2, the compound (2) is reacted with a known compound(7) in an inert solvent such as DMF, DMA, THF, DME, benzene, toluene orthe like in the presence of a base such as sodium hydride, potassiumhydride, sodium ethoxide or the like at 0° C. to about refluxtemperature of the solvent. Each of the compound (7) and the base isusually used in an equimolar amount to an about 5-fold molar amount,relative to the compound (2). The reaction is completed in about 1 toabout 50 hours.

Subsequently, the diester derivative (8) thus obtained is heated in aninert solvent such as water, water-DMF or the like at about refluxtemperature of the solvent for about 3 to about 50 hours, thusconverting to a monoester derivative (9).

The reactions for converting the compound (2) to the compound (8) andsynthesizing the compound (9) therefrom shown in Reaction Scheme-2 maybe sequentially carried out in the same reactor.

The compound (9) resulting from the above reaction is reacted with aknown aldehyde derivative (6) using an alkali such as lithiumdiisopropylamide, lithium dibutyl amide or the like in an inert solventsuch as THF, 1,4-dioxane or the like at temperatures in the range ofabout −100° C. to room temperature for about 5 to about 100 hours. Eachof the aldehyde derivative (6) and the alkali is used in an equivalentamount to a slight excess, relative to the compound (5).

wherein R¹, R², R³, X, Z and ψ are as defined above, R^(4a) is hydrogen,lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, loweralkoxy-carbonyl, lower alkyl, phenylthiomethoxycarbonyl, substitutedbenzyloxycarbonyl having 1 to 3 substituents selected from the groupconsisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which mayhave halogen or nitro as a substituent, or phenyl which may have halogenas a substituent.

In Reaction Scheme-3, the compound (2) is reacted with a known compound(10) in an inert solvent such as THF, 1,4-dioxane, diethyl ether, DMF orthe like in the presence of a base such as n-butyl lithium, n-hexyllithium, sodium hydride or the like at temperatures in the range ofabout −100° C. to room temperature. Each of the compound (10) and thebase is usually used in about a slight excess molar to an about 5-foldmolar amount, relative to the compound (2). The reaction is completed inabout 10 minutes to about 3 hours.

Subsequently, the compound (11) thus obtained is reacted with a knownaldehyde derivative (6) to convert to a compound (1d) of the presentinvention. This reaction can be carried out using an alkali such assodium hydride, potassium hydride, sodium ethoxide orpotassium-t-butoxide in an inert solvent such as dimethoxyethane,diethylene glycol dimethyl ether, t-butanol, THF or the like at roomtemperature to about reflux temperature of the solvent for about 1 toabout 150 hours. Each of the aldehyde derivative (6) and the alkali isused in an equivalent amount to a slight excess, relative to thecompound (11).

wherein R¹, R², R³ and ψ are as defined above and R^(4b) is hydrogen orlower alkyl.

In Reaction Scheme-4, the compound (2) is reacted with a known ketonecompound (12) in the presence of an alkali such as lithiumdiisopropylamide, lithium dibutyl amide or the like in an inert solventsuch as THF, 1,4-dioxane or the like at temperatures in the range ofabout −100° C. to room temperature for about 5 to about 100 hours. Eachof the ketone derivative (12) and the alkali is used in a slight molarexcess to an about 5-fold molar amount, relative to the compound (2). Ifnecessary, hexamethylphosphoric triamide may be added to the reactionsystem in a slight molar excess to an about 5-fold molar amount,relative to the compound (2).

Subsequently, the compound (13) thus obtained is subjected to areduction reaction in a lower alcohol inert solvent such as methanol,ethanol or the like using a boron hydride compound such as sodiumborohydride, or in an inert solvent such as diethyl ether, THF or thelike using an aluminum hydride compound such as lithium aluminumhydride. Each of the boron hydride compound and the aluminum hydridecompound is used in an amount of about 1 to about 6 equivalents,calculated as hydrides. The reaction is completed at temperatures in therange of about 0° C. to room temperature in about 10 minutes to about 3hours.

Subsequently, the alcohol derivative (14) thus obtained is converted toa compound (1e) of the present invention, for example, by either of thefollowing two methods.

(1) Dehydration Reaction With an Acid Catalyst

The compound (14) is treated in the presence of an acid catalyst such asp-toluenesulfonic acid, sulfuric acid or the like in an inert solventsuch as benzene, toluene, xylene or the like at temperatures in therange of room temperature to about reflux temperature of the solvent forabout 1 to about 10 hours. If necessary, an excess of an anhydrousinorganic salt such as anhydrous magnesium sulfate, anhydrous sodiumsulfate, anhydrous calcium chloride or the like may be added to thereaction system.

(2) Dehydrohalogenation Reaction After Halogenation

The compound (14) is treated with an equivalent amount to a slightequivalent excess of a halogenating agent such as thionyl chloride,thionyl bromide, phosphorus oxychloride or the like in an inert solventsuch as dichloromethane, 1,2-dichloroethane, diethyl ether or the like.An equivalent amount to a slight excess of a tertiary amine such aspyridine, lutidine, collidine, triethylamine or the like may be added tothe reaction system. The treatment reaction is carried out attemperatures in the range of 0° C. to room temperature for about 5minutes to about 2 hours.

Subsequently, the compound thus obtained is dehydrohalogenated. Thereaction can be carried out in an inert solvent such as benzene,toluene, xylene or the like using about an equimolar amount to an about3-fold molar amount of a deacidification agent such as1,8-diazabicyclo[5,4-0]-7-undecene (DBU), triethylamine,N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like, relativeto the starting compound. The reaction is usually carried out attemperatures in the range of 0° C. to room temperature and is completedin about 10 minutes to about 2 hours.

wherein R¹, R², R^(2a), R³ and Q are as defined above.

In Reaction Scheme-5, the compound (1f) is hydrolyzed in an inertsolvent such as methanol, ethanol or the like using an aqueous alkalisolution such as aqueous sodium hydroxide solution, aqueous potassiumhydroxide solution or the like. The aqueous alkali solution is used inan equivalent amount to a slight excess, relative to the compound (1f).The reaction is carried out at temperatures in the range of 0° C. toroom temperature and is completed in about 0.5 to about 10 hours.

wherein R¹, R², R^(2a), R³ and Q are as defined above.

In Reaction Scheme-6, the compound (1c) is decarboxylated by heating thecompound (1c) in an inert solvent such as benzene, toluene, xylene orthe like in the presence of an amine such as DBU, triethylamine,N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like, and athiol such as thiophenol, ethanethiol or the like at about refluxtemperature of the solvent for about 30 minutes to about 5 hours. Bothof the amine and thiol are used in a catalytic amount.

wherein R¹, R² and R³ are as defined above, Ω is lower alkyl,phenylthiomethyl, substituted benzyl having 1 to 3 substituents selectedfrom the group consisting of lower alkoxy, halogen and nitro, or phenylwhich may have halogen or nitro as a substituent.

In the above definition, the substituted benzyl having 1 to 3substituents selected from the group consisting of lower alkoxy, halogenand nitro includes, for example, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl, 3-ethoxybenzyl, 3-propoxybenzyl, 3-butoxybenzyl,3-pentyloxybenzyl, 3-hexyloxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl,4-chlorobenzyl, 4-bromobenzyl, 4-iodobenzyl, 4-fluorobenzyl,2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,3-dimethoxybenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl,3,5-dichlorobenzyl, 2,4-dinitrobenzyl, 3,5-dinitrobenzyl,2,3,4-trimethoxybenzyl, 2,3,5-trimethoxybenzyl, 2,3,6-trimethoxybenzyl,2,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3,4,5-trimethoxybenzyl,2,4,6-trichlorobenzyl, 2,4,6-trinitrobenzyl and the like.

The phenyl which may have halogen or nitro as a substituent includes2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,4-iodophenyl, 4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl,4-nitrophenyl and the like.

The conversion reaction of the compound (1h) to compound (1i) shown inReaction Scheme-7 is carried out, for example, by either of thefollowing two methods.

(1) Reaction With a Halide

The compound (1h) is reacted with a halide of the formula Ω-X (wherein Ωand X are as defined above) in an inert solvent such as DMF, DMA, THF,dichloromethane or the like in the presence of a deacidification agentsuch as triethylamine, N,N-dimethylaniline,4-(N,N-dimethylamino)pyridine or the like. Each of the halide and thedeacidification agent is used in about an equimolar amount to an about3-fold molar amount, relative to the compound (1h). The reaction isusually carried out at room temperature to reflux temperature of thesolvent for about 30 minutes to about 5 hours.

(2) Reaction With an Oxy Derivative

The compound (1h) is reacted with an oxy derivative of the formula Ω-OH(wherein Ω is as defined above) in an inert solvent such asdichloromethane, 1,2-dichloroethane or the like in the presence of adehydrating agent such as dicyclohexylcarbodiimide (DCC), diethoxyphosphoryl cyanide (DEPC) or the like. Each of the oxy derivative andthe dehydrating agent is used in an equivalent amount to a slightequivalent excess, relative to the compound (1h). The reaction isusually carried out at 0° C. to room temperature and is completed inabout 5 hours to about 100 hours.

wherein R¹, R² and R³ are as defined above, Σ is hydrogen, lower alkyl,benzyl, lower alkoxy-carbonyl-lower alkyl, halophenyl or 1-loweralkoxy-carbonyl-2-phenylethyl.

The lower alkoxy-carbonyl-lower alkyl group represented by Σ includes(C₁₋₆-alkoxy)carbonyl-(C₁₋₆-alkyl) groups. The halophenyl group includesa phenyl group having on the phenyl ring, a halogen atom selected fromfluorine, chlorine, bromine and iodine. The 1-loweralkoxy-carbonyl-2-phenylethyl group includes1-(C₁₋₆-alkoxy)carbonyl-2-phenylethyl.

The conversion reaction of the compound (1h) to a compound (1j) shown inReaction Scheme-8 is carried out by the following method. The compound(1h) is reacted with a chloroformic acid ester such as isobutylchloroformate, methyl chloroformate or the like in an inert solvent suchas THF, diethyl ether, 1,4-dioxane or the like in the presence of atertiary amine such as triethylamine, trimethylamine,N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine or the like toproduce a mixed acid anhydride. The mixed acid anhydride is reacted withan amine derivative represented by the formula Σ-NH₂ wherein Σ is asdefined above. Each of the composition for elimination, tertiary amineand amine derivative is used in an equivalent amount to a slightequivalent excess, relative to the compound (1h). The reaction treatmentwith the compound for elimination is usually carried out at temperaturesin the range of 0° C. to room temperature for about 10 minutes to about1 hour. The reaction treatment with the amine derivative is usuallycarried out at temperatures in the range of 0° C. to room temperaturefor about 30 minutes to about 10 hours. The reactions may besequentially carried out in the same reactor.

The conversion reaction of the compound (1h) to the compound (1j) shownin Reaction Scheme-8 may also be carried out in accordance with themethod (2) of Reaction Scheme-7 (Reaction with an oxy derivative), whichcomprises reacting the compound (1h) with an amine derivative of Σ-NH₂(wherein Σ is as defined above) in the presence of a dehydrating agent.The amounts of the amine derivative and the dehydrating agent and thereaction conditions may be the same as in the method (2) of ReactionScheme-7.

wherein R¹ is lower alkyl, thienyl or phenyl; one of R^(2b) and R^(3a)is hydrogen and the other is naphthyl, substituted phenyl having 1 to 3substituents selected from the group consisting of lower alkoxy,phenyl-lower alkoxy and hydroxyl, or phenyl which may have a substituentselected from the group consisting of N,N-di-lower alkylamino,halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy andhalogen.

The oxidation reaction of the compound (1k) shown in Reaction Scheme-9can be carried out using an oxidizing agent such as hydrogen peroxide,m-chloroperbenzoic acid, sodium periodate or the like in an inertsolvent such as acetic acid, dichloromethane, carbon tetrachloride orthe like. Using the oxidizing agent in an equivalent amount to a slightequivalent excess relative to the starting compound, a sulfinyl compound(n=1) is obtained by the oxidation reaction at 0° C. to room temperaturefor about 15 minutes to about 10 hours. To obtain a sulfonyl compound(n=2), the oxidizing agent is used in an amount of 2 equivalents or morerelative to the starting compound, optionally using a catalyst such assodium tungstate or the like, and the reaction is carried out attemperatures in the range of 0° C. to reflux temperature of the solventfor about 15 minutes to about 10 hours.

The desired compound wherein n=2 (sulfonyl compound) can also beproduced by oxidizing the compound wherein n=1 (sulfinyl compound) onceagain in a similar manner. The reaction can be carried out under any ofthe above-mentioned conditions.

wherein R¹, R⁵, Q and Z are as defined above.

The reaction between the compound (4) and known salicylaldehydederivative (15) shown in Reaction Scheme-10 can be carried out in asimilar manner as in the reaction between the compound (11) and aldehydederivative (6) shown in Reaction Scheme-3. The solvent and reactionconditions may also be the same as in the reaction between the compound(11) and aldehyde derivative (6). If necessary, an equivalent amount toa slight excess of a crown ether such as 18-crown-6 may be used in thereaction.

wherein R¹, R² and R³ are as defined above, R^(4c) is N-(loweralkoxy-carbonyl-lower alkyl)carbamoyl or N-(1-loweralkoxy-carbonyl-2-phenylethyl)carbamoyl, and R^(4d) is N-(carboxy-loweralkyl)carbamoyl or N-(1-carboxy-2-phenylethyl)carbamoyl.

According to Reaction Scheme-11, the compound (1n) obtainable by themethod shown in Reaction Scheme-8 is hydrolyzed to form a compound (1p).The hydrolysis of the compound (1n) can be carried out in a similarmanner as in the hydrolysis of the compound (1f) shown in ReactionScheme-5, thus giving the compound (1p) having a correspondinghydrolyzed group.

wherein R¹ and R⁴ are as defined above, one of R^(2c) and R^(3c) ishydrogen and the other is substituted phenyl having 1 to 3 benzyloxygroups and optionally further having 1 to 2 lower alkoxy groups, R^(2d)and R^(3d) correspond to R^(2c) and R^(3c) and one of R^(2d) and R^(3d)is a substituted phenyl group having hydroxyl groups in place ofbenzyloxy groups (i.e., substituted phenyl having 1 to 3 hydroxyl groupsand optionally further having 1 to 2 lower alkoxy groups).

As shown in Reaction Scheme-12, the compound (1q) havingbenzyloxy-substituted phenyl is hydrogenolized to convert benzyloxygroups into hydroxyl groups. The reaction can be carried out in an inertsolvent such as ethanol, methanol, ethyl acetate or the like in thepresence of a catalytic amount of a catalyst such as palladium-carbon,platinum oxide, Raney nickel or the like in an atmosphere of hydrogen ina stoichiometric amount or more at temperatures in the range of 0° C. toroom temperature. The reaction is completed in about 5 minutes to about1 hour, thus giving a compound (1r).

In the above reaction, it is preferable to promptly stop the reactionupon consumption of a stoichiometric amount of hydrogen so that doublebonds of carbon atoms bound to R^(2c) and R^(3c) of the startingcompound may not be hydrogenated.

The compounds obtained by the processes shown in the above ReactionSchemes can be easily isolated by conventional separation andpurification methods. Examples of such methods include adsorptionchromatography, preparative thin-layer chromatography,recrystallization, solvent extraction and the like.

The compounds of the invention can be formed into pharmaceuticallyacceptable acid addition salts. The compounds of the invention includesuch salts. Acids for use to form such acid addition salts are, forexample, inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid and the like and organic acids such as oxalic acid,fumaric acid, maleic acid, tartaric acid, citric acid, p-toluenesulfonicacid and the like. These acid addition salts can be formed according toconventional methods.

The compounds of the invention can be formed into alkali metal saltssuch as sodium salts, potassium salts or the like, alkaline earth metalsalts such as calcium salts, magnesium salts or the like and other saltssuch as copper salts or the like, by conventional methods. Such saltsalso constitute part of the compounds of the invention.

Some of the compounds of the invention exist as optical isomers having acarbon atom as an asymmetric center. Optical isomers in the form ofR-body, S-body and racemic body are included among the compounds of theinvention.

For use, the compounds of the invention are usually shaped into generaldosage forms for pharmaceutical compositions with pharmaceuticallyacceptable carriers. Examples of pharmaceutically acceptable carriersinclude conventional diluents or excipients such as fillers, volumebuilders, binders, humectants, disintegrators, surfactants, lubricantsand the like. These carriers are selectively used according to thedesired unit dosage form.

The unit dosage form for the pharmaceutical compositions of theinvention can be selected from a broad variety of forms according to theintended medical treatment. Typical examples are tablets, pills,powders, solutions, suspensions, emulsions, granules, capsules,suppositories, injections (solutions, suspensions, etc.), ointments, andthe like.

For preparing tablets by molding, usable as the above pharmaceuticallyacceptable carriers are excipients such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid and potassium phosphate; binders such as water,ethanol, propanol, simple syrup, glucose syrup, starch solution, gelatinsolution, carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose and polyvinyl pyrrolidone; disintegrators such as sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose,low-substituted hydroxypropyl cellulose, dry starch, sodium alginate,agar powder, laminaran powder, sodium hydrogen-carbonate and calciumcarbonate; surfactants such as polyoxyethylene sorbitan fatty acidesters, sodium lauryl sulfate and stearyl monoglyceride; disintegrationinhibitors such as sucrose, stearin, cacao butter and hydrogenated oil;absorption promoters such as quaternary ammonium base and sodium laurylsulfate; humectants such as glycerin and starch; adsorbents such asstarch, lactose, kaolin, bentonite and colloidal silicic acid; andlubricants such as purified talc, stearic acid salt, boric acid powderand polyethylene glycol.

The tablets may further be made into coated tablets such as sugar-coatedtablets, gelatin-coated tablets, enteric tablets, film-coated tablets,double-layered tablets or multiple-layered tablets.

For preparing pills by molding, usable as pharmaceutically acceptablecarriers are excipients such as glucose, lactose, starch, cacao butter,hydrogenated vegetable oil, kaolin and talc; binders such as gum arabicpowder, tragacanth powder, gelatin and ethanol; and disintegrators suchas laminaran and agar.

For formulating suppositories, usable as pharmaceutically acceptablecarriers are polyethylene glycol, cacao butter, a higher alcohol or itsesters, gelatin, semisynthetic glycerides and the like. The capsules areusually manufactured in a conventional manner by blending the compoundof the invention with one or more pharmaceutically acceptable carriersas exemplified above and encapsulating the mixture into hard gelatincapsule shells, soft capsule shells, etc.

When the pharmaceutical preparation is to be provided in an injectableform such as a solution, an emulsion or a suspension, the preparation ispreferably sterilized and rendered isotonic to the blood. Diluents foruse in such preparation are, for example, water, ethanol, macrogols,propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearylalcohol, polyoxyethylene sorbitan fatty acid esters and the like. Inthis case, sodium chloride, glucose or glycerin may be added to thepharmaceutical composition in an amount sufficient to provide anisotonic solution. Conventional solubilizers, buffers, anesthetics andthe like may also be added to the pharmaceutical composition.

Further, if desired, coloring agents, preservatives, aromatics, flavors,sweeteners or other medicines may be incorporated into thepharmaceutical composition.

For preparing ointments in the form of pastes, creams, gels, etc.,usable as diluents are white petrolatum, paraffin, glycerin, cellulosederivatives, polyethylene glycol, silicone, bentonite and the like.

The present inventors found that when a pyrazolo[1,5-a]pyrimidinederivative of formula (1) wherein R⁴ is carboxyl is used as an activeingredient and mixed with a suitable acid polymer, oral administrationof the resulting mixture (composition) improves permeability of theactive ingredient through the intestinal membrane. Examples of usefulacid polymers are aqueous solutions and suspensions of acid polymers ator below pH 6. Specific examples include hydroxypropyl methylcellulosephthalate, hydroxymethylcellulose acetate succinate, methacrylicacid/methacrylate copolymers and the like. Particularly preferred aremethacrylic acid/methacrylate copolymers (1:1) (e.g., trade name:Eudragit L100, product of Rohm Pharm. Co., Ltd.)

The proportion of the compound of the formula (1) of the invention(active ingredient) in the pharmaceutical preparation is not criticaland can be selected from a broad range. It is usually preferable for thecompound to account for about 1 to about 70 wt. % of the pharmaceuticalpreparation.

There is no limitation on the method for administering thepharmaceutical preparation. A proper method can be selected according tothe dosage form, patient's age, sex and other conditions, severity ofdisease, etc. For example, the tablets, pills, solutions, suspensions,emulsions, granules and capsules are administered by the oral route. Theinjections are administered singly or in admixture with glucose, aminoacid or like conventional infusions by the intravenous route or ifnecessary, administered singly by the intramuscular, intradermal,subcutaneous or intraperitoneal route. The suppositories areadministered intrarectally.

The dosage of the pharmaceutical preparation is suitably selectedaccording to the intended use, patient's age, sex and other conditions,severity of disease, etc. The dosage of the compound of the invention asthe active ingredient is preferably about 0.5 to about 20 mg per kg bodyweight a day for human adult. The pharmaceutical preparation may beadministered once a day or in 2-4 divided doses a day.

BEST MODE FOR CARRYING OUT THE INVENTION

Given below are Examples illustrating the production processes for thecompounds of the invention. Reference Examples illustrate preparationprocesses for the starting compounds (or intermediates) for preparingthe compounds of the invention.

REFERENCE EXAMPLE 1

12.0 g of 60% sodium hydride was added to 100 ml of DMF, followed bycooling to 0° C. Thereto was added 70.6 g of triethyl phosphonoacetate,followed by stirring at 0° C. for 1 hour and further stirring at roomtemperature for 4 hours. The mixture was cooled to 0° C. again and asolution of 30 g of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine in 20 mlof DMF was added dropwise, followed by stirring at 0° C. for 30 minutesand further stirring at room temperature for 65 hours. The reactionmixture was poured into 2 l of ice water. The aqueous layer was washedtwice with 600 ml of n-hexane and extracted with 100 ml of 5% aqueoussodium hydroxide solution. Then 300 ml of ethyl acetate and 42 g ofcitric acid were added to the extract and stirred at room temperaturefor 30 minutes, followed by extraction with ethyl acetate. The organiclayer was washed with water, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent; ethyl acetate:n-hexane=1:1). As aresult, 41 g of (5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)triethylphosphonoacetate was obtained as an oily product.

The following compounds were prepared in a similar manner as above.

(5-Methylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetate

(5-Ethylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetate

(5-n-Propylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetate

(5-n-Pentylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetate

(5-n-Hexylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetate

[5-(2-Thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]triethyl phosphonoacetate

[5-(3-Thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]triethyl phosphonoacetate

(5-Phenylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetate.

REFERENCE EXAMPLE 2

50 ml of 2% aqueous sodium hydroxide solution was added to 5 g of(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetateobtained in Reference Example 1, followed by stirring at 60° C. for 1.5hours. After addition of ice water, the reaction mixture was neutralizedwith 1.75 g of citric acid and extracted with chloroform. The organiclayer was collected, washed sequentially with water and saturatedaqueous sodium chloride solution and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent; ethyl acetate:n-hexane=1:2→2:1). As a result, 2.6 g of diethyl(5-n-butylpyrazolo-[1,5-a]pyrimidin-7-yl)methylphosphonate was obtainedas an oily product.

The following compounds were prepared in a similar manner as above.

Diethyl (5-methylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate

Diethyl (5-ethylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate

Diethyl (5-n-propylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate

Diethyl (5-n-pentylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate

Diethyl (5-n-hexylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate

Diethyl [5-(2-thienyl)pyrazolo[1,5-a]pyrimldin-7-yl]methylphosphonate

Diethyl [5-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]methylphosphonate

Diethyl (5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate.

Example 1

Preparation of(E)-5-n-butyl-7-[2-(3,4,5-trimethoxyphenyl)ethenyl]pyrazolo[1,5-a]pyrimidine

1.0 g of diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonate obtained inReference Example 2 and 0.66 g of 3,4,5-trimethoxybenzaldehyde weredissolved in 5.0 ml of ethanol, followed by cooling to 0° C. Thereto wasadded 3.8 ml of 5% aqueous potassium hydroxide solution, followed bystirring at 0° C. for 1 hour. After completion of the reaction, thecrystals precipitated were collected and washed with 10% aqueous ethanolsolution and recrystallized from ethanol. 0.72 g of the desired compoundwas obtained as crystals. The structure and melting point of thecompound obtained are shown in Table 1.

Examples 2-7

The compounds shown in Table 1 were prepared in a similar manner as inExample 1.

Examples 8-9

Preparation of(E)-5-n-butyl-7-[2-(4-chlorophenyl)ethenyl]pyrazolo[1,5-a]pyrimidine and(Z)-5-n-butyl-7-[2-(4-chlorophenyl)ethenyl]pyrazolo[1,5-a]pyrimidine

Using diethyl (5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)methylphosphonateobtained in Reference Example 2 and 4-chlorobenzaldehyde, a reaction wascarried out in a similar manner as in Example 1 and the crude productwas recrystallized from ethanol-water, thus giving an E compound (pureproduct). Subsequently, mother liquor was extracted with ethyl acetate,washed with water and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent; ethylacetate:n-hexane=1:4), thus giving a Z compound (pure product, acolorless oily product). The structure and melting point of thecompounds obtained are shown in Table 1.

Examples 10 and 11

The compounds shown in Table 1 were prepared in a similar manner as inExamples 8 and 9.

REFERENCE EXAMPLE 3

30.7 ml of n-butyl lithium (1.63 M, n-hexane solution) was diluted with35 ml of THF, and the diluted solution was cooled to −78° C. in anatmosphere of argon. Thereto was added a solution of 10.4 g of diethylmethylthiomethylphosphonate in 10 ml of THF, followed by stirring at−78° C. for 1 hour. Thereto was added dropwise a solution of 5 g of5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine in 5 ml of THF, followed bystirring at −78° C. for 1 hour. The reaction mixture was diluted withethyl acetate and washed sequentially with aqueous ammonium chloridesolution, water and saturated saline and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent; ethyl acetate:n-hexane=1:3→1:1). As a result, 5.9 g of diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate wasobtained as an oily product.

The following compounds were prepared in a similar manner as above.

Diethyl(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate

Diethyl(5-ethylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate

Diethyl(5-n-propylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate

Diethyl(5-n-pentylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate

Diethyl(5-n-hexylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate

Diethyl[5-(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]methylthiomethylphosphonate

Diethyl[5-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]methylthiomethylphosphonate

Diethyl(5-phenylpyrazoro[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonate

Diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)ethylthiomethylphosphonate

Diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-n-propylthiomethylphosphonate

Diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-n-butylthiomethylphosphonate

Diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-n-pentylthiomethylphosphonate

Diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-n-hexylthiomethylphosphonate.

Example 12

Preparation of(Z)-5-n-butyl-7-[1-methylthio-2-(3,4,5-trimethoxyphenyl)ethenyl]pyrazolo[1,5-a]pyrimidine

5.5 g of diethyl(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)methylthiomethylphosphonateobtained in Reference Example 3 was dissolved in 25 ml ofdimethoxyethane, followed by cooling to 0° C. Thereto was added 2.0 g ofpotassium-t-butoxide, followed by cooling to 0° C. Then 3.2 g of3,4,5-trimethoxybenzaldehyde was added, followed by stirring at roomtemperature for 15 minutes and further stirring at 60° C. for 3 hours.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The residue was diluted with ethyl acetate,washed sequentially with water and with saturated saline andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:2)and recrystallized from diethyl ether-n-hexane. 1.7 g of the desiredcompound was obtained as crystals. The structure and melting point ofthe compound obtained are shown in Table 1.

Examples 13-26

The compounds shown in Table 1 were prepared in a similar manner as inExample 12, using the compounds obtained in Reference Example 1 asstarting compounds.

REFERENCE EXAMPLE 4

Using diethyl ethylphosphonate and5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine, the procedure was carriedout in a similar manner as in Reference Example 3, thus giving diethyl1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonate.

The following compounds were prepared in a similar manner as above.

Diethyl 1-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonate

Diethyl 1-(5-ethylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonate

Diethyl 1-(5-n-propylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonate

Diethyl 1-(5-n-pentylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonate

Diethyl 1-(5-n-hexylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonate

Diethyl 1-[5-(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]ethylphosphonate

Diethyl 1-[5-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-yl]ethylphosphonate

Diethyl 1-(5-phenylpyrazoro[1,5-a]pyrimidin-7-yl)ethylphosphonate

Diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)propylphosphonate

Diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)butylphosphonate

Diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)pentylphosphonate

Diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)hexylphosphonate

Diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)heptylphosphonate.

Example 27

Preparation of(E)-5-n-butyl-7-[1-(3,4,5-trimethoxyphenyl)propen-2-yl]pyrazolo[1,5-a]pyrimidine

Using diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)ethylphosphonateas a starting compound, the procedure was carried out in a same manneras in Example 12, thus giving the compound shown in Table 1.

Examples 28-29

Preparation of (E)-ethyl2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(4-chlorophenyl)acrylateand (Z)-ethyl2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(4-chlorophenyl)acrylate

Using (5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetateobtained in Reference Example 1 and 4-chlorobenzaldehyde, a reaction wascarried out in the same manner as in Example 12. The crude productobtained was purified by silica gel column chromatography (eluent; ethylacetate:n-hexane=1:10→1:3), whereby a Z compound was obtained from theformer fraction and an E compound was obtained from the latter fraction.The structure and melting point of the compounds obtained are shown inTable 1.

Examples 30-39

The compounds shown in Table 1 were prepared in a similar manner as inExamples 28 and 29.

Example 40

Preparation of (E)2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(3,4,5-trimethoxyphenyl)acrylicAcid

18.0 g of the compound obtained in Example 31 was dissolved in 180 ml ofethanol. Then 36 ml of 5% aqueous sodium hydroxide solution was added,followed by stirring at room temperature for 4 hours. The reactionmixture was concentrated under reduced pressure and then acidified byaddition of water and 6.38 g of citric acid, followed by extraction withethyl acetate. The organic layer was collected, washed sequentially withwater and with saturated saline and concentrated under reduced pressure.The residue was recrystallized from ethyl acetate-n-hexane at roomtemperature. As a result, 13.65 g of the desired compound having amelting point of 117-120° C. (decomposition) was obtained as crystals.

The crystals thus obtained were dissolved in ethyl acetate. Whileheating the solution in a hot bath, n-hexane was gradually added,whereby crystals were precipitated. The crystals had a melting point of153° C. or higher (decomposition) and had the same structure as theabove compound.

The structure and melting point of the compound obtained are shown inTable 1.

The compound obtained in Example 30 was hydrolyzed in a similar manneras above. The same compound as above was obtained.

Examples 41-59

The compounds shown in Table 1 were prepared in a similar manner as inExample 40.

Example 60

Preparation of(E)-5-n-butyl-7-[2-(4-methylthiophenyl)-ethenyl]pyrazolo[1,5-a]pyrimidine

0.50 g of the compound obtained in Example 44 was dissolved in 10 ml oftoluene, followed by adding 0.1 ml of thiophenol and 0.1 ml of DBU. Themixture was refluxed for 1 hour. The reaction mixture was allowed tocool, diluted with ethyl acetate, washed sequentially with water andwith saturated saline and concentrated under reduced pressure. Theresidue was recrystallized from n-hexane. 0.28 g of the desired compoundwas obtained as crystals. The structure and melting point of thecompound obtained are shown in Table 1.

Examples 61-69

The compounds shown in Table 1 were prepared in a similar manner as inExample 60.

Example 70

Preparation of (E)-ethyl2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(3,4,5-trimethoxyphenyl)acrylate

2.0 g of the compound obtained in Example 40 was dissolved in 10 ml ofDMF. To the solution were added 1.0 ml of triethylamine and 0.78 ml ofethyl iodide, followed by stirring at 60° C. for 2 hours. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure. The residual crystals were separated from theconcentrate by filtration and washed with diethyl ether. The filtrateand washing fluid were washed sequentially with water and with saturatedsaline and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent; ethylacetate:n-hexane=1:4→1:1) and recrystallized from diethylether-n-hexane. 1.55 g of the desired compound (the same compound as inExample 31) was obtained as crystals.

Examples 71-75

The compounds shown in Table 1 were prepared in a similar manner as inExample 70.

Example 76

Preparation of(E)-2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-4-chlorophenyl-3-(3,4,5-trimethoxyphenyl)acrylate

0.50 g of the compound obtained in Example 40 and 0.16 g of4-chlorophenol were dissolved in 4 ml of dichloromethane, followed bycooling to 0° C. Thereto was added 1 ml of dichloromethane solutioncontaining 0.25 g of DCC, followed by stirring at 0° C. for 1 hour andat room temperature for 60 hours. After completion of the reaction, thereaction mixture was diluted with ethyl acetate and the insolublematerial was separated by filtration. The filtrate was washedsequentially with aqueous sodium hydroxide solution, water and saturatedsaline and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent; ethylacetate:n-hexane=1:4→1:2) and recrystallized from diethylether-n-hexane. 0.48 g of the desired compound was obtained as crystals.The structure and melting point of the compound obtained are shown inTable 1.

Examples 77-79

The compounds shown in Table 1 were prepared in a similar manner as inExample 76.

Example 80

Preparation of(E)-2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-N-ethyl-3-(3,4,5-trimethoxyphenyl)acrylamide

0.70 g of the compound obtained in Example 40 was dissolved in 5 ml ofTHF, followed by cooling to 0° C. Thereto were added 0.28 ml oftriethylamine and 0.24 ml of isobutyl chloroformate, followed bystirring at 0° C. for 30 minutes. A solution prepared by diluting 0.94ml of THF solution of 2M ethylamine with 2 ml of THF was added at 0° C.,followed by stirring at 0° C. for 1 hour and at room temperature for 2hours. After completion of the reaction, the reaction mixture wasdiluted with ethyl acetate, washed sequentially with water and withsaturated saline and concentrated under reduced pressure. The residualcrude crystals were recrystallized from ethyl acetate-n-hexane. 0.62 gof the desired compound was obtained as crystals. The structure andmelting point of the compound obtained are shown in Table 1.

Examples 81-87

The compounds shown in Table 1 were prepared in a similar manner as inExample 80.

Example 88

Preparation of(Z)-5-n-butyl-7-[1-methylsulfinyl-2-(3,4,5-trimethoxyphenyl)ethenyl]pyrazolo[1,5-a]pyrimidine

0.50 g of the compound obtained in Example 12 was dissolved in 5 ml ofacetic acid. To the solution was added 0.14 ml of 30% aqueous hydrogenperoxide solution, followed by stirring at room temperature for 4 hours.The reaction mixture was diluted with dichloromethane, washedsequentially with water, sodium bicarbonate solution and saturatedsaline and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent; ethylacetate:n-hexane=1:1→ethyl acetate→dichloroethane:methanol=10:1) andrecrystallized from ethyl acetate-n-hexane. 0.38 g of the desiredcompound was obtained as crystals. The structure and melting point ofthe compound obtained are shown in Table 1.

Example 89

Preparation of(E)-5-n-butyl-7-[1-methylsulfonyl-2-(3,4,5-trimethoxyphenyl)ethenyl]pyrazolo[1,5-a]pyrimidine

0.50 g of the compound obtained in Example 12 was dissolved in 3 ml ofacetic acid. To the solution was added 0.34 ml of aqueous 30% hydrogenperoxide solution, followed by stirring at 60° C. for 4 hours. Thereaction mixture was diluted with dichloromethane, washed sequentiallywith sodium bicarbonate solution, water and saturated saline andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent; ethyl acetate:n-hexane=2:3) andrecrystallized from ethyl acetate-n-hexane. 0.24 g of the desiredcompound was obtained as crystals. The structure and melting point ofthe compound obtained are shown in Table 1.

Example 90

Preparation of5-n-butyl-7-(6,7,8-trimethoxycoumarin-3-yl)pyrazolo[1,5-a]pyrimidine

0.21 g of 3,4,5-trimethoxysalicylaldehyde was dissolved in 3 ml of THF.To the solution was added 0.12 g of potassium-t-butoxide, followed bystirring at room temperature for 10 minutes. Thereto was added 2 ml ofTHF solution containing 0.35 g of(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)triethyl phosphonoacetateobtained in Reference Example 1, followed by stirring at roomtemperature for 10 minutes. Then 0.28 g of 18-crown-6 was added,followed by stirring at room temperature for 120 hours. The reactionmixture was diluted with ethyl acetate, washed sequentially with waterand with saturated saline and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent; ethylacetate:n-hexane=1:2) and recrystallized from ethyl acetate-n-hexane.0.14 g of the desired compound was obtained as crystals. The structureand melting point of the compound obtained are shown in Table 1.

Example 91

The compound shown in Table 1 was prepared in a similar manner as inExample 90.

TABLE 1

Me = methyl, Et = ethyl, i-Pr = isopropyl, n-Bu = n-butyl, Ph = phenylExample Melting point (° C.) No. R¹ R² R³ R⁴ (Recrystalization solvent)1 n-Bu H

H 83˜85 (Ethanol-n-hexane) 2 n-Bu H Ph H 74˜76 (Ethanol-water) 3 n-Bu H

H 69˜71 (Ethanol-water) 4 n-Bu H

H 116˜118 (Ethanol-water) 5 n-Bu H

H 67˜69 (Ethyl acetate-n-hexane) 6 n-Bu H

H 55˜57 (Ethanol-water) 7 n-Bu H

H 131˜133 (Ethyl acetate-n-hexane) 8 n-Bu H

H 92˜94 (Ethanol-water) 9 n-Bu

H H Oily product (NMR 1) 10 n-Bu H

H 67˜69 (Ethanol-water) 11 n-Bu

H H 62˜64 (Ethanol-water) 12 n-Bu H

—SMe 71˜73 (n-Hexane) 13 n-Bu Ph H —COOEt Oily product (NMR 2) 14 n-Bu

H —COOEt Oily product (NMR 3) 15 n-Bu

H —COOEt Oily product (NMR 4) 16 n-Bu

H —COOEt Oily product (NMR 5) 17 n-Bu

H —COOEt Oily product (NMR 6) 18 n-Bu

H —COOEt Oily product (NMR 7) 19 n-Bu

H —COOEt Oily product (NMR 8) 20 n-Bu

H —COOEt Oily product (NMR 9) 21 n-Bu

H —COOEt Oily productd (NMR 10) 22 Ph

H —COOEt Oily product (NMR 11) 23 n-Bu

H —COOEt 78˜80 (Ethanol-water) 24 n-Bu

H —COOEt 106˜108 (Ethanol-water) 25 n-Bu

H —COOEt Oily product (NMR 12) 26 n-Bu

H —COOEt Oily product (NMR 13) 27 n-Bu H

—Me 122˜124(Hydrochloride) (Ethyl acetate) 28 n-Bu H

—COOEt Oily product (NMR 14) 29 n-Bu

H —COOEt Oily product (NMR 15) 30 n-Bu H

—COOEt Oily product (NMR 16) 31 n-Bu

H —COOEt 50˜52 (n-Hexane) 32 n-Bu H

—COOEt 72-75 (n-Hexane) 33 n-Bu

H —COOEt Oily product (NMR 17) 34

H

—COOEt 166˜168 (Ethyl acetate-n-hexane) 35

H —COOEt Oily product (NMR 18) 36 n-Bu H

—COOEt 96˜98 (ethyl acetate-n-hexane) 37 n-Bu

H —COOEt 116˜118 (Ethyl acetate-n-hexane) 38 n-Bu H

—COOEt 118˜120 (n-Hexane) 39 n-Bu

H —COOEt 103˜105 (Ethyl acetate-n-hexane) 40 n-Bu

H —COOH 117˜120 (Decomposition) (Ethyl acetate-n-hexane) 41 n-Bu

H —COOH 149˜150 (Decomposition) (Ethyl acetate-n-hexane) 42 n-Bu Ph H—COOH Oily product (NMR 19) 43 n-Bu

H —COOH 157˜158 (Decomposition) (Ethyl acetate-n-hexane) 44 n-Bu

H —COOH 133˜135 (Decomposition) (Ethyl acetate-n-hexane) 45 n-Bu

H —COOH 165˜166 (Decomposition) (Ethyl acetate-n-hexane) 46 n-Bu

H —COOH 140˜142 (Decomposition) (Ethyl acetate-n-hexane) 47 n-Bu

H —COOH 130˜132 (Decomposition) (Ethyl acetate-n-hexane) 48 n-Bu

H —COOH 166˜168 (Decomposition) (Ethyl acetate-n-hexane) 49 n-Bu

H —COOH Oily product (NMR 20) 50 n-Bu

H —COOH 110˜113 (Decomposition) (Ethyl acetate-n-hexane) 51 n-Bu

H —COOH 155˜156 (Decomposition) (Ethyl acetate-n-hexane) 52 n-Bu

H —COOH Hydrochloride, 130˜132 (Decomposition) (Ethyl acetate) 53 Ph

H —COOH 206˜208 (Decomposition) (Chloroform-ethyl acetate) 54

H —COOH 212˜214 (Decomposition) (Chloroform-ethyl acetate) 55 n-Bu

H —COOH 168˜169 (Decomposition) (Ethyl acetate-n-hexane) 56 n-Bu

H —COOH 158˜159 (Decomposition) (Ethyl acetate-n-hexane) 57 n-Bu

H —COOH 160˜161 (Decomposition) (Ethyl acetate-n-hexane) 58 n-Bu

H —COOH Oily product (NMR 21) 59 n-Bu

H —COOH 195˜196 (Decomposition) (Chloroform-ethyl actate) 60 n-Bu H

H 89˜91 (n-Hexane) 61 n-Bu H

H 66˜68 (n-Hexane) 62 n-Bu H

H 134˜136 (Decomposition) (Ethyl acetate-n-hexane) 63 Ph H

H 119˜121 (Ethyl acetate-n-hexane) 64

H

H 133˜135 (Ethyl acetate-n-hexane) 65 n-Bu H

H 125˜127 (Ethyl acetate-n-hexane) 66 n-Bu H

H 89˜91 (Ethyl acetate-n-hexane) 67 n-Bu H

H 71˜73 (Ethanol-water) 68 n-Bu H

H 117˜119 (Toluene) 69 n-Bu H

H 64˜66 (Ethanol-n-hexane) 70 (=31) n-Bu

H —COOEt 50˜52 (n-Hexane) 71 n-Bu

H —COOCH₂SPh Oily product (NMR 22) 72 n-Bu

H

Oily product (NMR 23) 73 n-Bu

H

99˜101 (Ethyl acetate-n-hexane) 74 n-Bu

H

89˜91 (Ethyl acetate-n-hexane) 75 n-Bu

H

Oily product (NMR 24) 76 n-Bu

H

78˜80 (Diethyl ether-n-hexane) 77 n-Bu

H —COOPh Oily product (NMR 25) 78 n-Bu

H

110˜111 (Diethyl ether-n-hexane) 79 n-Bu

H

123˜125 (Diethyl ether-n-hexane) 80 n-Bu

H —CONHEt 150˜152 (Ethyl acetate-n-hexane) 81 n-Bu

H —CONH₂ 134˜136 (Ethyl acetate-n-hexane) 82 n-Bu

H —CONHMe 128˜130 (Ethyl acetate-n-hexane) 83 n-Bu

H —CONH—i—Pr 126˜128 (Ethyl acetate-n-hexane) 84 n-Bu

H —CONHCH₂Ph 154˜155 (Diethyl ether) 85 n-Bu

H —CONHCH₂CO₂Et 135˜136 (Ethyl acetate-n-hexane) 86 n-Bu

H

101˜103 (Ethyl acetate-n-hexane) 87 n-Bu

H

161˜163 (Ethyl acetate-n-hexane) 88 n-Bu H

—SOMe 100˜102 (Ethyl acetate-n-hexane) 89 n-Bu

H —SO₂Me 97˜100 (Ethyl acetate-n-hexane) 90 n-Bu H

127˜118 (Ethyl acetate-n-hexane) 91 n-Bu H

116˜118 (Ethyl acetate-n-hexane)

NMR1(CDCl₃, δ ppm):

0.89(3H, t, J=7.2), 1.2-1.4(2H, m), 1.5-1.6(2H, m), 2.65(2H, t, J=7.4),6.49(1H, s), 6.64(1H, d, J=2.5), 7.08(1H, dd, J=12.6, 0.5), 7.14(1H, d,J=12.6), 8.10(1H, d, J=2.5).

NMR2(CDCl₃, δ ppm):

0.88(3H, t, J=7.2), 1.18(3H, t, J=7.2), 1.2-1.4(2H, m), 1.6-1.7(2H, m),2.76(2H, t, J=7.4), 4.24(2H, q, J=7.2), 6.51(1H, s), 6.65(1H, d, J=2.5),7.1-7.3(3H, m), 8.07(1H, d, J=2.5), 8.17(1H, s).

NMR3(CDCl₃, δ ppm):

0.91(3H, t, J=7.2), 1.17(3H, t, J=6.9), 1.2-1.4(2H, m) 1.6-1.8(2H, m),2.80(2H, t, J=7.4), 3.75(3H, s), 4.22(2H, q, J=6.9), 6.58(1H, s),6.65(1H, d, J=2.2), 6.68(2H, d, J=8.7), 6.96(2H, d, J=8.7), 8.06(1H, d,J=2.2), 8.11(1H, s).

NMR4(CDCl₃, δ ppm):

0.91(3H, t, J=7.4), 1.18(3H, t, J=6.9), 1.3-1.4(2H,m), 1.6-1.8(2H, m),2.41(3H, s), 2.79(2H, t, J=7.7), 4.23(2H, q, J=6.9), 6.55(1H, s),6.65(1H, d, J=2.2), 6.91(2H, d, J=8.7), 6.99(2H, d, J=8.7), 8.06(1H, d,J=2.2), 8.10(1H, s).

NMR5(CDCl₃, δ ppm):

0.92(3H, t, J=7.4), 1.17(3H, t, J=7.2), 1.3-1.4(2H, m), 1.7-1.8(2H, m),2.81(2H, t, J=7.7), 2.94(6H, s), 4.21(2H, q, J=7.2), 6.42(2H, d, J=9.2),6.64(1H, d, J=2.5), 6.65(1H, s), 6.88(2H, d, J=9.2), 8.04(1H, d, J=2.5),8.07(1H, s).

NMR6(CDCl₃, δ ppm):

0.87(3H, t, J=7.4), 1.19(3H, t, J=6.9),1.2-1.4(2H, m), 1.6-1.7(2H,m),2.76(2H, t, J=7.4), 4.26(2H, q, J=6.9), 6.45(1H, s),6.67(1H, d,J=2.5),7.12(2H, d, J=7.9), 7.44(2H, d, J=7.9), 8.08(1H, d, J=2.5),8.18(1H, s).

NMR7(CDCl₃, δ ppm):

0.91(3H, t, J=7.2), 1.17(3H, t, J=6.9), 1.3-1.4(2H, m), 1.7-1.8(2H, m),2.81(2H, t, J=7.7), 4.22(2H, q, J=6.9), 5.91(2H, s), 6.36(1H, d, J=1.5),6.58(1H, s), 6.6-6.7(3H, m), 8.06(1H, s), 8.06(1H, d, J=1.5).

NMR8(CDCl₃, δ ppm):

0.88(3H, t, J=7.4), 1.18(3H, t, J=7.2), 1.2-1.4(2H, m), 1.6-1.7(2H, m),2.75(2H, t, J=7.7), 3.77(3H, s), 3.81(3H, s), 3.89(3H, s), 4.24(2H, q,J=7.2), 6.30(2H, d, J=1.0), 6.47(1H, s), 6.63(1H, d, J=2.2), 8.07(1H, d,J=2.2), 8.32(1H,s).

NMR9(CDCl₃, δ ppm):

0.80(3H, t, J=7.4), 1.21(3H, t, J=7.2), 1.2-1.3(2H, m), 1.6-1.7(2H, m),2.74(2H, t, J=7.7), 4.27(2H, q, J=7.2), 6.54(1H, s), 6.68(1H, d, J=2.2),6.90(1H, dd, J=1.7, 8.7), 7.4-7.6(3H, m), 7.6-7.8(3H, m), 8.09(1H, d,J=2.2), 8.33(1H, s).

NMR10(CDCl₃, δ ppm):

0.96(3H, t, J=7.4), 1.19(3H, t, J=7.2), 1.4-1.5(2H, m), 1.7-1.9(2H, m),2.87(2H, t, J=7.7), 4.23(2H, q, J=7.2), 6.36(1H, dd, J=2.0, 3.5),6.49(1H, d, J=3.5), 6.62(1H, d, J=2.2), 6.71(1H, s), 7.20(1H, d, J=2.0),7.91(1H, s), 8.00(1H, d, J=2.2).

NMR11(CDCl₃, δ ppm):

1.23(3H, t, J=7.2), 3.44(6H, s), 3.77(3H, s), 4.28(2H, q, J=7.2),6.26(2H, s), 6.79(1H, d, J=2.2), 7.21(1H, s),7.4-7.6(3H, m), 8.0-8.1(2H,m), 8.15(2H, brs).

NMR12(CDCl₃, δ ppm):

0.86(3H, t, J=7.4), 1.20(3H, t, J=7.2), 1.2-1.3(2H, m), 1.6-1.7(2H, m),2.72(2H, t, J=7.4), 3.22(3H, s), 3.61(3H, s), 4.25(2H, q, J=7.2),6.15(1H, d, J=2.7), 6.43(1H, s), 6.62(1H, d, J=2.2), 6.7-6.9(2H, m),8.09(1H, d, J=2.2), 8.35(1H,s).

NMR13(CDCl₃, δ ppm):

0.91(3H, t, J=7.2), 1.21(3H, t, J=7.2), 1.3-1.4(2H, m), 1.6-1.8(2H, m),2.80(2H, t, J=7.4), 3.30(3H, s), 3.83(3H, s), 4.25(2H, q, J=7.2),6.22(1H, d, J=2.0), 6.60(1H, s), 6.65(1H, d, J=2.2), 6.70(1H, d, J=8.2),6.79(1H, dd, J=2.0, 8.2), 8.06(1H, d, J=2.2), 8.12(1H,s).

NMR14(CDCl₃, δ ppm):

0.98(3H, t, J=7.2), 1.14(3H, t, J=7.2), 1.4-1.5(2H, m), 1.7-1.8(2H, m),2.87(2H, t, J=7.7), 4.25(2H, q, J=7.2), 6.62(1H, d, J=2.2), 6.78(1H, s),7.37(2H, d, J=8.7), 7.45(2H, d, J=8.7), 7.69(1H, s), 8.04(1H, d, J=2.2).

NMR15(CDCl₃, δ ppm):

0.90(3H, t, J=7.2), 1.18(3H, t, J=7.2), 1.2-1.4(2H, m), 1.6-1.7(2H, m),2.78(2H, t, J=7.7), 4.24(2H, q, J=7.2), 6.50(1H, s), 6.66(1H, d, J=2.4),6.94(2H, d, J=6.7), 7.14(2H, d, J=6.7), 8.07(1H, d, J=2.4), 8.11(1H, s).

NMR16(CDCl₃, δ ppm):

0.95(3H, t, J=7.4), 1.15(3H, t, J=6.9), 1.4-1.5(2H, m), 1.8-1.9(2H, m),2.87(2H, t, J=7.7), 3.88(6H, s), 3.91(3H, s), 4.25(2H, q, J=6.9),6.62(1H, d, J=2.5), 6.78(1H, s), 6.82(2H, s), 7.72(1H, s),8.05(1H,d,J=2.5).

NMR17(CDCl₃, δ ppm):

0.90(3H, t, J=7.4), 1.22(3H, t, J=7.2), 1.3-1.4(2H, m), 1.6-1.8(2H, m),2.79(2H, t, J=7.7), 4.27(2H, q, J=7.2), 6.55(1H, s), 6.61(1H, d, J=2.5),7.10(1H, dd, J=4.2, 7.9), 7.11(1H, d, J=7.9), 7.53(1H, dt, J=1.7, 7.9),7.99(1H, d, J=2.5), 8.16(1H, s), 8.27(1H, dd, J=1.7, 4.2).

NMR18(CDCl₃, δ ppm):

1.22(3H, t, J=7.2), 3.45(6H, s), 3.77(3H, s), 4.27(2H, q, J=7.2),6.28(2H, s), 6.72(1H, d, J=2.5), 7.08(1H, s), 7.12(1H, dd, J=3.7, 4.9),7.51(1H, dd, J=1.0, 4.9), 7.60(1H, dd, J=1.0, 3.7), 8.11(1H, d, J=2.5),8.14(1H, s).

NMR19(CDCl₃, δ ppm):

0.87(3H, t, J=7.4), 1.2-1.4(2H, m), 1.6-1.7(2H, m), 2.76(2H, t, J=7.4),6.54(1H, s), 6.68(1H, d, J=2.5), 6.9-7.0(2H, m), 7.1-7.3(3H, m),8.10(1H, d, J=2.5), 8.22(1H, s).

NMR20(CDCl₃, δ ppm):

0.87(3H, t, J=7.2), 1.2-1.4(2H, m), 1.6-1.8(2H, m), 2.76(2H, t, J=7.4),3.77(3H, s), 3.81(3H, s), 3.88(3H, s), 6.30(2H, s), 6.52(1H, s),6.66(1H, d, J=2.0), 8.08(1H, d, J=2.0), 8.42(1H, s).

NMR21(CDCl₃, δ ppm):

0.85(3H, t, J=7.2), 1.2-1.3(2H, m), 1.5-1.7(2H, m), 2.72(2H, t, J=7.7),3.20(3H, s), 3.61(3H, s), 6.13(1H, d, J=3.0), 6.48(1H, s), 6.65(1H, d,J=2.5), 6.73(1H, d, J=9.2), 6.80(1H, dd, J=3.0, 9.2), 8.12(1H, d,J=2.5), 8.45(1H, s).

NMR22(CDCl₃, δ ppm):

0.90(3H, t, J=7.2), 1.2-1.4(2H, m), 1.6-1.7(2H, m), 2.77(2H, t, J=7.7),3.44(6H, s), 3.79(3H, s), 5.48(2H, s), 6.19(2H, s), 6.57(1H, s),6.65(1H, d, J=2.5),7.1-7.2(5H, m), 8.06(1H, d, J=2.5), 8.14(1H, s).

NMR23(CDCl₃, δ ppm):

0.90(3H, t, J=7.4), 1.3-1.4(2H, m), 1.6-1.8(2H, m), 2.78(2H, t, J=7.7),3.44(6H, s), 3.75(3H, s), 3.78(3H, s), 5.21(2H, s), 6.18(2H, s),6.58(1H, s), 6.64(1H, d, J=2.2), 6.7-6.9(3H, m), 7.22(1H, t, J=7.9),8.09(1H, d, J=2.2), 8.14(1H, s).

NMR24(CDCl₃, δ ppm):

0.89(3H, t, J=7.2), 1.2-1.4(2H, m), 1.6-1.7(2H, m), 2.78(2H, t, J=7.7),3.44(6H, s), 3.77(6H, s), 3.78(3H, s), 3.82(3H, s), 5.16(2H, s),6.18(2H, s), 6.38(2H, s), 6.59(1H, s), 6.64(1H, d, J=2.5), 8.08(1H, d,J=2.5), 8.14(1H, s).

NMR25(CDCl₃, δ ppm):

0.91(3H, t, J=7.4), 1.3-1.5(2H, m), 1.7-1.8(2H, m), 2.82(2H, t, J=7.7),3.47(6H, s), 3,81(3H, s), 6.26(2H, s), 6.66(1H, d, J=2.2), 6.70(1H, s),7.1-7.4(5H, m), 8.14(1H, d, J=2.2), 8.28(1H, s).

Example 92

The compound shown in Table 2 was prepared in a similar manner as inExample 60, using a compound prepared in a similar manner as inReference Example 1 as a starting compound.

Examples 93-94

The compounds shown in Table 2 were prepared in a similar manner as inExamples 8 and 9.

Examples 95-98

The following compounds were prepared in a similar manner as inReference Example 3.

Diethyl 1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)benzylphosphonate;

Diethyl1-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-(4-chlorobenzyl)phosphonate.

The compounds shown in Table 2 were prepared in a similar manner as inExample 12, using the above compounds and(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)trimethyl phosphonoacetateprepared in a similar manner as in Reference Example 1.

Examples 99-100

The compounds shown in Table 2 were prepared by hydrolyzing thecompounds obtained in Examples 85 and 86 in a similar manner as inExample 40.

Examples 101-105

The following compounds were prepared in a similar manner as in Example12, using (5-methylpyrazolo[1,5-a]pyrimidin-7-yl)trimethylphosphonoacetate, (5-ethylpyrazolo[1,5-a]pyrimidin-7-yl)trimethylphosphonoacetate and (5-n-propylpyrazolo[1,5-a]pyrimidin-7-yl)trimethylphosphonoacetate prepared in a similar manner as in Reference Example 1.

(E) methyl2-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(3,4,5-trimethoxyphenyl)acrylate

(E) methyl2-(5-ethylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(3,4,5-trimethoxyphenyl)acrylate

(E) methyl2-(5-n-propylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(3,4,5-trimethoxyphenyl)acrylate.

The above compounds and the compounds obtained in Examples 97 and 98were hydrolyzed in a similar manner as in Example 40, thus giving thecompounds shown in Table 2.

Example 106-108

The compounds obtained in Examples 101-103 were decarboxylated in asimilar manner as in Example 60, thus giving the compounds shown inTable 2.

Example 109

Preparation of (E)2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylicacid

2 g of the compound obtained in Example 105 was dissolved in 20 ml ofethanol. To the solution was added 0.2 g of 5% palladium-carbon,followed by purging the reaction system with hydrogen and stirring atroom temperature for 30 minutes (hydrogen consumption: about 94 ml).After completion of the reaction, 5% palladium-carbon was separated byfiltration and the filtrate was concentrated. The residue was purifiedby silica gel column chromatography (eluent; chloroform yl)trimethylphosphonoacetate obtained in a similar manner as in Reference Example 1was reacted with 3-benzyloxy-4,5-dimethoxybenzaldehyde in a similarmanner as in Example 12. (E) methyl2-(5-n-butylpyrazolo[1,5-a]pyrimidin-7-yl)-3-(3-benzyloxy-4,5-dimethoxyphenyl)acrylicacid was obtained.

Subsequently, the compound was hydrolyzed in a similar manner as inExample 109, thus giving the compound shown in Table 2.

TABLE 2

Me = methyl, Et = ethyl, i-Pr = isopropyl, n-Pr = n-propyl, n-Bu =n-butyl, Ph = phenyl Example Melting point (° C.) (Recrystalization No.R¹ R² R³ R⁴ solvent)  92 n-Bu H

H 64˜66 (n-Hexane)  93 n-Bu H —C≡C—Ph H 79˜83 (Ethanol-water)  94 n-Bu—C≡C—Ph H H 49˜50 (Ethanol-water)  95 n-Bu

H Ph 103-105 (Diisopropyl ether)  96 n-Bu

H

89˜92 (Diethyl ether-n-hexane)  97 n-Bu —C≡C—Ph H —COOMe 100˜103(Diisopropyl ether)  98 n-Bu

H —COOMe 134˜137 (Methanol)  99 n-Bu

H —CONHCH₂CO₂H >113 (Decomposition) (Ethyl acetate-n- hexane) 100 n-Bu

H

127˜130 (Diethyl ether-n-hexane) 101 Me

H —COOH >172 (Decomposition) (Ethyl acetate-n- hexane) 102 Et

H —COOH >165 (Decomposition) (Ethyl acetate-n- hexane) 103 n-Pr

H —COOH >175 (Decomposition) (Ethyl acetate-n- hexane) 104 n-Bu —C≡C—PhH —COOH >155 (Decomposition) (Ethyl acetate-n- hexane) 105 n-Bu

H —COOH >155 (Decomposition) (Ethyl acetate-n- hexane) 106 Me H

H 157˜160 (Ethanol) 107 Et H

H 164˜166 (Ethyl acetate-n-hexane) 108 n-Pr H

H 96˜99 (Ethyl acetate-n-hexane) 109 n-Bu

H —COOH >152 (Decomposition) (Ethyl acetate-n- hexane) 110 n-Bu

H —COOH >185 (Decomposition) (Ethyl acetate-n- hexane)

Given below are Formulation Examples for manufacturing pharmaceuticalcompositions containing the compound of the invention as an activeingredient.

Formulation Example 1

Manufacture of Tablets

Tablets (1000 tables), each containing as an active ingredient 250 mg ofthe compound of the invention obtained in Example 10, were manufacturedaccording to the following formulation:

Amount Component (g) Compound of the invention obtained in Example 10250 Lactose (Japanese pharmacopoeia) 33.5 Corn starch (Japanesepharmacopoeia) 16.5 Carboxymethyl cellulose calcium 12.5 (Japanesepharmacopoeia) Methyl cellulose (Japanese pharmacopoeia) 6.0 Magnesiumstearate (Japanese pharmacopoeia) 1.5 Total 320.0

According to the above formulation, the compound of the inventionobtained in Example 10, lactose, corn starch and carboxymethyl cellulosecalcium were well blended and granulated using aqueous methyl cellulosesolution. The granulated mixture was passed through a 24-mesh sieve, andthe granules under the sieve were mixed with magnesium stearate andcompression-molded to give the desired tablets.

Formulation Example 2

Manufacture of capsules

Hard gelatin capsules (1000 capsules), each containing as an activeingredient 250 mg of the compound of the invention obtained in Example40, were manufactured according to the following formulation:

Amount Component (g) Compound of the invention obtained in Example 40250 Crystalline cellulose (Japanese pharmacopoeia)  30 Corn starch(Japanese pharmacopoeia)  17 Talc (Japanese pharmacopoeia)  2 Magnesiumstearate (Japanese pharmacopoeia)  1 Total 300

According to the above formulation, the ingredients were finelypulverized and blended to give a homogeneous mixture. This mixture wasfilled into proper-sized gelatin capsule shells for oral administrationto provide the desired capsules.

Given below are Pharmacological Test Examples in which the compounds ofthe invention were tested.

Pharmacological Test Example 1

Using 6-week-old male S.D. rats (7 rats in each group), the painthreshold of each rat's left hind paw plantar was measured using anAnalgesy-Meter (product of Unicom) in accordance with theRandall-Sellitto method [Randall, L. O. and Sellitto, J. J., Arch. Int.Pharmacodyn., 111, 409 (1957)]. The value thus obtained was termed“pre-value”.

One hour after the measurement of the pre-value, a 5% gum arabicsuspension containing the compound of the invention was orallyadministered to the rats of the test group in an amount of 10 ml/kg,whereas a 5% gum arabic suspension (not containing the compound of theinvention) was orally administered to the rats of the control group inan amount of 10 ml/kg.

One hour later, a physiological saline solution containing substance P(25 ng/0.1 ml) was subcutaneously injected into the left hind pawplantar of each rat.

The pain threshold of each rat's left hind paw was measured in the samemanner as above at predetermined time intervals from the substance Pinjection. The measured value was termed “post-value”.

The recovery (%) of the pain threshold was calculated from thepost-values and the pre-values of the test group and the control group,by means of the following formula:${{Recovery}\quad {of}\quad {pain}\quad {threshold}\quad (\%)} = {\frac{\begin{matrix}\begin{matrix}{{\text{(}{Test}\quad {group}\quad {average}\quad {post}\text{-}{value}\text{)}} -}\end{matrix} \\{\text{(}{Control}\quad {group}\quad {average}\quad {post}\text{-}{value}\text{)}}\end{matrix}}{\begin{matrix}\begin{matrix}{{\text{(}{Control}\quad {group}\quad {average}\quad {pre}\text{-}{value}\text{)}} -} \\{\text{(}{Control}\quad {group}\quad {average}\quad {post}\text{-}{value}\text{)}}\end{matrix}\end{matrix}} \times 100}$

Table 3 shows the results (the highest recovery %).

TABLE 3 Example Recovery Time of measurement No. (%) (minutes later)  147.8 60  8 36.2 30 10 58.7 60 12 41.5 60 40 47.2 60 43 46.3 30 45 40.460 46 48.9 60 47 57.1 30 62 50.0 30 65 30.1 30 66 32.2 60 74 50.3 15 7860.1 15 79 41.2 60 98 44.7 60 99 32.2 60 103  54.8 60 105  50.4 60 109 52.1 60 110  58.0 60

The results presented in Table 3 clearly demonstrate that the compoundsof the present invention have potent analgesic effects.

Industrial Applicability

The pyrazolo[1,5-a]pyrimidine derivatives according to the presentinvention have potent analgesic effects and are useful as analgesics.

What is claimed is:
 1. A pyrazolo[1,5-a]pyrimidine derivativerepresented by the following formula (1)

wherein R¹ is lower alkyl, phenyl or thienyl; one of R² and R³ ishydrogen and the other is naphthyl, furyl, pyridyl, styryl,phenylethynyl, substituted phenyl having 1 to 3 substituents selectedfrom the group consisting of lower alkoxy, phenyl-lower alkoxy andhydroxyl, or phenyl which may have a substituent selected from the groupconsisting of lower alkylthio, N,N-di-lower alkylamino,halogen-substituted lower alkyl, phenyl, nitro, methylenedioxy andhalogen; R⁴ is hydrogen, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, carboxyl, lower alkoxy-carbonyl, lower alkyl,phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3substituents selected from the group consisting of lower alkoxy, halogenand nitro, phenoxycarbonyl which may have halogen or nitro as asubstituent, carbamoyl, N-lower alkyl-carbamoyl, N-benzyl-carbamoyl,N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl, N-(carboxy-loweralkyl)carbamoyl, N-halophenylcarbamoyl, N-(1-loweralkoxy-carbonyl-2-phenylethyl)carbamoyl,N-(1-carboxy-2-phenylethyl)carbamoyl, phenyl which may have halogen as asubstituent, or the group

wherein R¹, R² and R³ are as defined above; when R² is hydrogen, R³ andR⁴ may conjointly represent a group represented by

wherein the R⁵s are the same or different and independently representhydrogen or lower alkoxy.
 2. The pyrazolo[1,5-a]pyrimidine derivativeaccording to claim 1 which is selected from: (i) compounds wherein R¹ islower alkyl; and (ii) compounds wherein R¹ is phenyl or thienyl, one ofR² and R³ is hydrogen and the other is substituted phenyl having 1 to 3lower alkoxy groups as substituents and R⁴ is hydrogen, carboxyl orlower alkoxy-carbonyl.
 3. The pyrazolo[1,5-a]pyrimidine derivativeaccording to claim 2 which is selected from: (1a) compounds defined in(i) of claim 2 wherein R¹ is lower alkyl and R⁴ is hydrogen, carboxyl orlower alkoxy-carbonyl; (1b) compounds defined in (i) of claim 2 whereinR¹ is lower alkyl and one of R² and R³ is hydrogen and the other isphenyl having 1 to 3 lower alkoxy groups as substituents, R⁴ is loweralkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl,phenylthiomethoxycarbonyl, substituted benzyloxycarbonyl having 1 to 3substituents selected from the group consisting of lower alkoxy, halogenand nitro, phenoxycarbonyl which may have halogen or nitro as asubstituent, carbamoyl, N-lower alkyl-carbamoyl, N-benzylcarbamoyl,N-(lower alkoxy-carbonyl-lower alkyl)carbamoyl, N-(carboxy-loweralkyl)carbamoyl, N-halophenylcarbamoyl, N-(1-loweralkoxy-carbonyl-2-phenylethyl)carbamoyl, or the group

wherein R¹, R² and R³ are as defined in formula (1); and (1c) compoundsdefined in (i) of claim 2 wherein R¹ is lower alkyl and R² is hydrogenand R³ and R⁴ conjointly represent a group represented by

wherein the R⁵s are the same or different and independently representhydrogen or lower alkoxy.
 4. The pyrazolo[1,5-a]pyrimidine derivativeaccording to claim 3 wherein R¹ is n-butyl.
 5. Thepyrazolo[1,5-a]pyrimidine derivative according to claim 2 which isselected from the compounds (ii) of claim 2 wherein R¹ is phenyl orthienyl, one of R² and R³ is hydrogen and the other is phenyl having 1to 3 lower alkoxy groups as substituents and R⁴ is hydrogen, carboxyl orlower alkoxy-carbonyl.
 6. The pyrazolo[1,5-a]pyrimidine derivativeaccording to claim 1 which is selected from: (i) compounds wherein R¹ isn-butyl, R² is hydrogen, R³ is naphthyl, pyridyl, phenyl having 1 to 3lower alkoxy groups as substituents or halogen-substituted phenyl and R⁴is hydrogen or lower alkylthio; and (ii) compounds wherein R¹ isn-propyl or n-butyl, R² is substituted phenyl having 1 to 3 substituentsselected from the group consisting of lower alkoxy, phenyl-lower alkoxyand hydroxyl, or phenyl which may have a substituent selected from thegroup consisting of N,N-di-lower alkylamino, halogen-substituted loweralkyl and halogen, R³ is hydrogen and R⁴ is carboxyl, loweralkoxy-carbonyl, phenylthiomethoxycarbonyl, substitutedbenzyloxycarbonyl having 1 to 3 substituents selected from the groupconsisting of lower alkoxy, halogen and nitro, phenoxycarbonyl which mayhave halogen or nitro as a substituent, or the group

wherein R¹, R² and R³ are as defined above.
 7. Thepyrazolo[1,5-a]pyrimidine derivative according to claim 6 which isselected from: (i) compounds defined in (i) of claim 6 wherein R³ ispyridyl and R⁴ is hydrogen; and (ii) compounds defined in (ii) of claim6 wherein R¹ is n-butyl, R² is phenyl having three lower alkoxy groupsas substituents or phenyl having two lower alkoxy groups and onehydroxyl group as substituents.
 8. The pyrazolo[1,5-a]pyrimidinederivative according to claim 7 which is selected from: (i) compoundsdefined in (i) of claim 7 wherein R³ is 2-pyridyl; and (ii) compoundsdefined in (ii) of claim 7 wherein R² is 3,4,5-trimethoxyphenyl and R⁴is carboxyl.
 9. A pharmaceutical composition comprising an effectiveamount of the pyrazolo[1,5-a]pyrimidine derivative of claim 1 and apharmaceutically acceptable carrier.
 10. The pharmaceutical compositionaccording to claim 9 which is an analgesic composition.
 11. A method forrelieving pain in a patient in need of such pain relief, which comprisesadministering to the patient an effective amount of thepyrazolo[1,5-a]pyrimidine derivative of claim 1.